The pathogenesis of human tuberculosis (TB) is unknown, as only a small fraction of infected individuals develop clinical disease. Proof-of-principle was recently obtained that human genetic variability may account for inter-individual clinical variability upon exposure to Mycobacterium tuberculosis (Mtb). However, the molecular basis of predisposition to TB in most patients has remained elusive. This application aims to identify the human genetic variants which control the development of clinical TB in Morocco. The two key clinical phenotypes will be investigated: disseminated TB in children and pulmonary TB in adults. Our working hypothesis is that pediatric TB results from Mendelian disorders affecting immunity to primary infection by Mtb, whereas adult TB reflects a more complex genetic predisposition, affecting immunity to latent Mtb. Population samples have been collected since 1995 in Morocco, a highly endemic region for TB. Also, the first child with Mendelian predisposition to TB as well as the first human locus linked with pulmonary TB on chromosome 8 were both identified in Morocco. The experimental strategy will combine Mendelian and complex genetics approaches, with candidate gene and genome-wide (GW) investigations. The patients with TB are being enrolled and immunologically characterized in Morocco using fresh blood samples, whereas the molecular genetic studies using cell lines derived from the patients will be conducted in New York. The genomic data are being generated in Montreal and the statistical analysis will be performed in Paris. Preliminary data indicate that IL-12Rb1 deficiency is a relatively common genetic etiology of pediatric TB. Moreover, novel pediatric TB-predisposing genes have been identified by GW linkage studies. In pulmonary TB, preliminary results of both the ongoing ultra-fine association mapping of the linked chromosome 8 region and GW association study show several interesting signals. A large replication case/control sample is being enrolled and will allow us to identify the true associated polymorphisms. All variants of interest (rare mutations and common polymorphisms) will be validated immunologically at the molecular and cellular level, using cutting-edge techniques. RELEVANCE: We aim to decipher the human genetic variants that account for development of clinical TB, providing a long-awaited understanding of its pathogenesis. These findings will have major clinical implications for the control of TB, both for identification of new prevention strategies (novel vaccines and optimal clinical trials) and for development of new treatments (restoration of deficient immune responses by circumventing genetic defect).